OVERALL - PROJECT SUMMARY The present application is the continuation of CA140043 for a new grant cycle. Progress made during the past four years identified a new role of mitochondrial metabolism in tumor progression (Project 1), dissected the function of integrin-mediated cell adhesion in prostate cancer invasion (Project 2), and elucidated transcriptional circuitries of bone metastatic disease (Project 3). As a whole, the Program had a multiplier effect for prostate cancer research. The original specific aims were met, impactful collaborative publications appeared in the peer-reviewed literature, and a translational goal of merging mechanistic understanding of prostate cancer progression with credentialing new therapeutic candidates for metastatic disease was fulfilled. Building on these accomplishments, the present continuation application has been significantly restructured. Brought back to a single physical location in Philadelphia with a rich environment for prostate cancer research, the continuation of CA140043 stresses innovation and focuses on emerging new paradigms of prostate cancer progression. The overarching goal is to elucidate new mechanisms of metastatic competency in prostate cancer, and identify ?actionable? therapeutic targets for late'stage disease. Project 1 (Project Leader, Dr. Altieri) will define a novel pathway of spatiotemporal mitochondrial bioenergetics, which fuels membrane dynamics of cell motility and prostate cancer invasion. Project 2 (Project Leader, Dr. Languino) will elucidate the role of prostate cancer-released exosomes as novel mediators of integrin-dependent tumor cell motility. Project 3 (Project Leader, Dr. Gabrilovich) is a new addition to the Program, and will characterize the role of mitochondrial reprogramming in the function and homing of Myeloid-Derived Suppressor Cells (MDSC) to primary and pre-metastatic tumor sites during prostate cancer progression. An Administration and Biostatistics core (Core A) will function as a research enhancer for the overall Program, ensuring scientific integration, input from advisory bodies, access to patient material, biostatistics support for the three Projects, and timely financial and administrative oversight. A unique Mass Spectrometry core (Core B) will support metabolomics profiling and quantitative proteomics of regulatory protein complexes, secretomes and proteomes in prostate cancer cells and MDSC. Overall, the Program builds on a decades-long history of collaboration among its experienced investigators, a cost-effective organizational infrastructure designed to maximize integration and reduce redundancies, and an intellectually-stimulating environment for collaborative prostate cancer research. This integrated discovery platform was enthusiastically received by the reviewers during the first evaluation of the application. Critical Program components (Cores, Integration) were found to have essentially no flaws, and recommendations with the experimental approaches of the three Projects have been addressed with inclusion of considerable new preliminary data, refocusing of experimental plans, and clarification of data analysis and interpretation. In line with the strong productivity of CA140043 during its first budget cycle, the investigators on this Program have continued to assiduously work together throughout the review process, publishing five additional collaborative papers, with five more collaborative manuscripts currently under review. Building on these accomplishments, and thank to the input of the reviewers, the amended application is now ideally poised to fulfill its specific aims, deliver on scientific innovation and transform our understanding of metastatic competency in prostate cancer. The results have the potential to revolutionize clinical practice in advanced disease, especially now that immunotherapy has emerged as a promising treatment in several malignancies, and targeting tumor metabolism has passed proof-of-concept and entered clinical testing.